The cell therapy market had revenue exceeding one billion dollars, with significant growth expected. While autologous cells are ideal to avoid immune rejection, allogeneic sources are attractive for diseases in which autologous cells are not readily available due to disease (e.g., Type 1 Diabetes (T1D)). Allogeneic islet transplantation for the treatment of T1D, which affects an estimated 1.5 million Americans, is an experimental therapy with limited tissue availability, with allogeneic stem cell-derived -cells showing great promise. In the previous funding for this grant, we developed microporous scaffolds to support engraftment of the transplanted islets at a clinically translatable extrahepatc site, and demonstrated the ability to modulate the local environment in order to maximize engraftment of transplanted cells. In this proposal, we investigate the induction of immune tolerance via biomaterials for allogeneic cell donors, which would avoid the long-term use of immunosuppressive drugs. Immunosuppressive drugs are currently used for solid organ and cell transplantation to prevent rejection, which leads to the non-specific immune suppression and may be diabetogenic. We propose a two-pronged approach: i) microporous scaffolds that locally modulate the immune response, and ii) i.v. infused particles delivering tolerogenic allogeneic antigens that systemically modulate the immune response. Our previous funding period supported the development of scaffolds to create an environment that supports islet engraftment, and Aim 1 of this proposal extends those results by locally delivering factors to modulate the immune response. Locally providing anti-inflammatory cytokines, chemokines may redirect immune cells away from an inflammatory phenotype in order to interrupt inflammation at an early stage. Importantly, these cytokines may limit APC activation and migration, which may decrease activation of CD4+ helper and CD8+ killer T cells that are responsible for graft rejection. We anticipate that these scaffolds may reduce the number of islets necessary for transplantation and facilitate tolerance induction by particles carrying donor antigen (Aim 2). Specific Aim 2 will investigate particle-based modulation of systemic anti-donor adaptive immune response for effective donor-specific tolerance induction for islet transplantation. Preliminary studies have demonstrated the capacity of PLG particles carrying solubilized donor antigens (PLG-dAg). Antigen isolation and loading into the particles will be investigated for their tolerogenic effects on APC function, along with the specificity and stability of transplant tolerance. We hypothesize that functionalized PLG-dAg effectively target and tolerize host APCs, and consequently induce stable and donor-specific transplant tolerance. Taken together, we anticipate that the scaffold microenvironment and antigen-loaded particles can synergize to effectively induce tolerance, which will reduce the number of islets needed for transplantation, and will enable allogeneic transplantation without immunosuppression, which would be a significant advance enabling numerous cell therapies.